Herceptin/trastuzumab is a monoclonal antibody that selectively targets the Her2 protein and remains the standard of care for Her2-positive breast cancer. Nevertheless, the biological processes altered by trastuzumab to impede cancer progression are presently unclear. Results from our preliminary studies show that trastuzumab causes cellular senescence in both cultured breast cancer cells and tumors derived from human patients who have undergone treatment in adjuvant therapy. This observed senescent phenotype is associated with several hallmarks of senescence including an inability to proliferate, induction of the cell cycle inhibitors p16 and p21, senescence-associated -galactosidase activity, and upregulation of the secreted proteins IGFBP3 and IGFBP5. Previous studies have indicated that high-level expression of the insulin-like growth factor 1 receptor (IGF1R) is associated with a lower response rate to trastuzumab. Consistent with this, elevated levels of IGF1R expression and phosphorylation were found in trastuzumab-resistant breast cancer cells following Her2 inhibition. Importantly, trastuzumab resistance can be overcome by combining trastuzumab with either a selective IGF1R inhibitor or recombinant IGFBPs, resulting in cellular senescence. Collectively, these results reveal the biological underpinnings of trastuzumab's clinical efficacy and suggest a practical approach for the treatment of Her2-positive, trastuzumab-resistant breast cancer. Capitalizing on these new findings, we propose the following two specific aims to explore the molecular basis that distinguish breast cancer patients who are sensitive to trastuzumab from those who are resistant. Aim 1 will assess the potential contributions of several mechanisms that may control the expression level of IGF1R associated with sensitivity/resistance to trastuzumab. Aim 2 will explore whether tyrosine kinase receptors, in addition to IGF1R, could be involved in the development of a trastuzumab-resistant phenotype. Together results from these exploratory experiments will lay the foundation a systemic analysis of molecular determinants at the mechanistic level for sensitivity and resistant to this standard therapy for Her2-positive breast cancer can be conducted in the future.